Multiple lines of evidence point to the importance of genetic risk factors in the development of cardiovascular disease (CVD). Recent genome-wide association studies (GWAS) have been successful in identifying common variants influencing CVD and its risk factors, but these variants explain only a small portion of the total heritable rik. Rare, functional variants (like those found in the coding, or exonic, regions of the genome) may explain additional heritability. The overall objective of this career development proposal is to identify exonic variants associated with sub-clinical CVD traits. We will perform these studies in the Old Order Amish (OOA), a population that is uniquely suited for this approach because rare, exonic variants that entered the population on a single chromosome are likely to be present in multiple individuals due to genetic drift and therefore easier to find than in the outbred Caucasian populations. To identify these rare variants, we will identify exonic variants in OOA individuals first, through the use of an exome genotyping chip and second, by using sequencing data. We will then test these variants for association with sub-clinical CVD traits and extend our analysis to non-Amish subjects. After identifying variants of interest, we will conduct genotype-directed participant recruitment to further characterize sub-clinical CVD traits in variant carrier. This research plan was designed to complement my training objectives which are to receive additional training in: 1) cardiovascular disease epidemiology, 2) statistical methods relevant to next generation sequencing methodologies and mixed model development and 3) patient-oriented clinical research. This K01 application will promote my career development by providing protected time to learn the targeted mentored skills and will facilitate my transition ino an independent investigator in the field of cardiovascular disease genetic epidemiology.